At present, all commercially available spermicidal contraceptives have detergent ingredients that disrupt cell membranes. These include the neutral surfactants isononyl-phenyl-polyoxyethylene (9) ether or nonoxynol-9 (N-9), p-menthanyl-phenyl-polyoxyethylene (8,8) ether or menfegol, and isooctyl-phenyl-polyoxyethylene (9) ether or octoxynol-9 (O-9) (Digenis G A, et al., Pharm Dev Technol, 1999;4:421-30; Furuse K, et al., J Pharmacobiodyn, 1983;6:359-72.) The detergent-type vaginal spermicide, N-9, available without a prescription, is the most commonly used spermicidal contraceptive in the UK and USA (OTC Panel, Federal Register, 1980;45:82014-49; Chantler E., Brit Fam Plann, 1992;17:118-9.) Worldwide, the cationic surfactant benzalkonium chloride and the anionic detergent sodium docusate (dioctyl sodium sulphosuccinate) are also used as vaginal spermicides (Mendez F, et al., Contraception, 1986;34:353-62.) N-9, sodium oxychlorosene, and benzalkonium chloride, have been used as gels, suppositories, ovules, sponges, or film. N-9 has been in use for more than 30 years in creams, gels, foams and condom lubricants. However, in several large studies for users of N-9, the average 6-month pregnancy rate is 26%, and the first-year pregnancy rates range from 11 to 31%. Thus, N-9 is approximately 75% effective in preventing pregnancy (Trussell J, et al. Stud Fam Plann, 1987;18:237-83; Kulig J W, Ped Clinic North Am, 1989;36:717-30; Raymond E, et al., Obstet Gynecol, 1999;93:896-903).
The spermicidal activities of these surfactants are associated with their structural affinity to the membrane lipids (Schill W B, et al., Andrologia, 1981;13:42-9; Helenious A, et al., Biochem Biophys Acta, 1975;415:29-79). Therefore, the major drawback of using N-9 or other currently used surfactants is their detergent-type effect on epithelial cells and normal vaginal flora. N-9 displays antiviral and spermicidal activities only at cytotoxic doses (D'Cruz O J, et al., Mol Hum Reprod, 1999;5:421-32; D'Cruz O J, et al., Biol Reprod, 2000;62:37-44). Frequent use of N-9 as a vaginal contraceptive/microbicide has been associated with an increased risk of vaginal or cervical infection, irritation, or ulceration (Niruthisard S R, et al., Sex Transm Dis, 1991;18:176-79; Rekart M L, Defic Syndr, 1992;5:425-27; Roddy R E, et al., Int J STD & HIV, 1993;4:165-70; Weir S S, et al., Genitourin Med, 1995;71:78-81). Detergent-type spermicides alter vaginal bacteria or flora, and lead to an increased risk of opportunistic infections (Hooten T M, et al., JAMA, 1991;265:64-9.; Stafford M K, J Acquir Immune Defic Syndr Hum Retrovirol, 1998;17:327-31.; Rosenstein I J, et al. J Infect Dis, 1998;177:1386-90.; Patton D L, et al., Sex Trans Dis, 1996;23:489-93.) Such opportunistic infections are known to enhance the susceptibility of the ectocervical epithelium and the endocervical mucosa to HIV-1 infection (Augenbraun M H, et al., Infect Dis Clin North Am, 1994; 8:439-48.) Chemical irritation that disrupts the vaginal mucosa may actually enhance the risk of vaginal transmission of sexually transmitted diseases (STDs) including HIV-1, by mucosal erosion and local inflammation (Weir S S, et al., Genitourin Med, 1995;71:78-81.;. Kreiss J, JAMA, 1992;268:477-82.). In a study conducted among commercial sex workers in Nairobi, in which some of the women used N-9 containing sponges, a significantly higher rate of genital ulceration and HIV-1 seroconversion was found compared with those not using N-9 (Kreiss J, JAMA, 1992;268:477-82.).
Furthermore, recent clinical trials have shown that vaginal contraceptive preparations containing N-9 have no effect on the transmission of HIV/AIDS and other STDs when provided as part of an overall program to prevent heterosexual transmission of HIV/AIDS (Hira S K, et al, Int J STD AIDS, 1997;8:243-50.; Roddy R E, et al., N Engl J Med, 1998;339:504-10.) Since heterosexual transmission of HIV-1 is the predominant mode of the epidemic spread of HIV, new, effective, and safe vaginal spermicides lacking detergent-type membrane toxicity may offer significant clinical advantage over the currently available detergent-type spermicides.
Because vaginal spermicides would likely be used repeatedly over decades, an ideal spermicide should have an established safety record and lack genital epithelial toxicity. Moreover, it should be inexpensive and be produced from commonly available resources and should have a broad specificity for solubilizing drugs effective for prevention of sexual transmission of several STDs including HIV-1.
Therefore, there is a continuing need for new and better spermicidal formulations.